Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTH6G1CV)

• DOT Name: Membrane-associated progesterone receptor component 2 (PGRMC2)
• Synonyms: Progesterone membrane-binding protein; Steroid receptor protein DG6
• Gene Name: PGRMC2
• Related Disease:
  Neoplasm
  Adenocarcinoma
  Advanced cancer
  Breast adenocarcinoma
  Hepatocellular carcinoma
• UniProt ID: PGRC2_HUMAN
• Pfam ID: PF00173
• Sequence:
  MAAGDGDVKLGTLGSGSESSNDGGSESPGDAGAAAEGGGWAAAALALLTGGGEMLLNVAL
  VALVLLGAYRLWVRWGRRGLGAGAGAGEESPATSLPRMKKRDFSLEQLRQYDGSRNPRIL
  LAVNGKVFDVTKGSKFYGPAGPYGIFAGRDASRGLATFCLDKDALRDEYDDLSDLNAVQM
  ESVREWEMQFKEKYDYVGRLLKPGEEPSEYTDEEDTKDHNKQD
• Function: Required for the maintenance of uterine histoarchitecture and normal female reproductive lifespan. May serve as a universal non-classical progesterone receptor in the uterus (Probable). Intracellular heme chaperone required for delivery of labile, or signaling heme, to the nucleus. Plays a role in adipocyte function and systemic glucose homeostasis. In brown fat, which has a high demand for heme, delivery of labile heme in the nucleus regulates the activity of heme-responsive transcriptional repressors such as NR1D1 and BACH1.
• Tissue Specificity: Expressed by endometrial glands and stroma (at protein level) . Detected in urine (at protein level) .
• KEGG Pathway: Neuroactive ligand-receptor interaction (hsa04080)
• Reactome Pathway:
  RAC2 GTPase cycle (R-HSA-9013404)
  RHOD GTPase cycle (R-HSA-9013405)
  RHOG GTPase cycle (R-HSA-9013408)
  RAC3 GTPase cycle (R-HSA-9013423)
  RHOA GTPase cycle (R-HSA-8980692)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Adenocarcinoma	DIS3IHTY	Limited	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[2]
Breast adenocarcinoma	DISMPHJ0	Limited	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[1]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Membrane-associated progesterone receptor component 2 (PGRMC2).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Membrane-associated progesterone receptor component 2 (PGRMC2).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Membrane-associated progesterone receptor component 2 (PGRMC2).	[18]

17 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Membrane-associated progesterone receptor component 2 (PGRMC2).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Membrane-associated progesterone receptor component 2 (PGRMC2).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Membrane-associated progesterone receptor component 2 (PGRMC2).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Membrane-associated progesterone receptor component 2 (PGRMC2).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Membrane-associated progesterone receptor component 2 (PGRMC2).	[8]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Membrane-associated progesterone receptor component 2 (PGRMC2).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Membrane-associated progesterone receptor component 2 (PGRMC2).	[10]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Membrane-associated progesterone receptor component 2 (PGRMC2).	[11]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Membrane-associated progesterone receptor component 2 (PGRMC2).	[12]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of Membrane-associated progesterone receptor component 2 (PGRMC2).	[13]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Membrane-associated progesterone receptor component 2 (PGRMC2).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Membrane-associated progesterone receptor component 2 (PGRMC2).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Membrane-associated progesterone receptor component 2 (PGRMC2).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Membrane-associated progesterone receptor component 2 (PGRMC2).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Membrane-associated progesterone receptor component 2 (PGRMC2).	[20]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Membrane-associated progesterone receptor component 2 (PGRMC2).	[21]
Resorcinol	DMM37C0	Investigative	Resorcinol increases the expression of Membrane-associated progesterone receptor component 2 (PGRMC2).	[22]

References

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• [3] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
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• [5] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [6] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [10] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [11] Inorganic arsenic exposure promotes malignant progression by HDAC6-mediated down-regulation of HTRA1. J Appl Toxicol. 2023 Aug;43(8):1214-1224. doi: 10.1002/jat.4457. Epub 2023 Mar 11.
• [12] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [13] Folate deficiency in normal human fibroblasts leads to altered expression of genes primarily linked to cell signaling, the cytoskeleton and extracellular matrix. J Nutr Biochem. 2007 Aug;18(8):541-52. doi: 10.1016/j.jnutbio.2006.11.002. Epub 2007 Feb 22.
• [14] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [17] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [18] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [19] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [20] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [21] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [22] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.